Please use this identifier to cite or link to this item: http://doi.org/10.25358/openscience-5353
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dc.contributor.authorAlkanawati, Mohammad Shafee-
dc.date.accessioned2020-11-19T12:15:53Z-
dc.date.available2020-11-19T12:15:53Z-
dc.date.issued2020-
dc.identifier.urihttps://openscience.ub.uni-mainz.de/handle/20.500.12030/5357-
dc.description.abstractThe design of nanocarriers for drug delivery requires tremendous efforts and planning to ensure the preparation method is compatible with the drug used as the payload, that the resulting nanocarriers are biocompatible, ideally biodegradable and display in vivo stability. Furthermore, they need to be able to target specific cells, be uptaken by the cells, and able to release the payload after cell uptake. All those requirements need to be met with a fabrication method that can be scaled up to meet the requirements in terms of scale, quality, and reproducibility associated with the pharmaceutical industry. The main goals of this thesis were to develop a process that can be used for the large scale synthesis of high-quality nanocarriers and to develop new crosslinking chemistry possibilities to produce nanocarriers suitable for the encapsulation of sensitive payloads. In this thesis, microfluidization was used to prepare large quantities of nanocarriers synthesized based on the interfacial crosslinking of precursor droplets formed by inverse miniemulsion. Those nanocarriers were prepared in high quality and large quantity in a reproducible manner with the possibility to tune the size of the nanocarriers (section 4.1). The versatility of the microfluidization method was also demonstrated by using different precursor polymers such as polysaccharide, proteins, and lignin, and by using different crosslinking strategies (section 4.1). The microfluidization approach to prepare the precursor droplets was then combined with new crosslinking strategies. Bio-orthogonal reactions involving the reaction between reactive carbonyls and hydrazide derivatives were used to prepare stimuli-responsive nanocarriers (sections 4.2 and 4.3). Rather than using an unselective reaction that can react with complex and sensitive payloads, a strategy based on the selective reaction between dextran functionalized either with aldehyde or terminal ketone groups and polyfunctional hydrazide derivative was used to produce nanocapsules (Section 4.2) or nanogels (section 4.3). This reaction is highly suitable because it is a selective reaction, has a sufficiently high reaction rate, and since the stability of the resulting hydrazone linkages is pH-sensitive, those new nanocarriers enabled vi the release of the payloads it in a spatiotemporally controlled manner. The dissociation of the hydrazone crosslinking points in mildly acidic conditions was responsible for the controlled release of the cargos. In the first approach (section 4.2), the hydrazone network was built by interfacial crosslinking of inverse miniemulsion droplets to form nanocarriers. The water droplets contained the dextran precursor, and the crosslinker poly(styrene-co-methyl hydrazide) was dissolved in the continuous toluene phase. These nanocarriers with capsule morphology were able to both encapsulate model hydrophilic compounds and release them upon changing the acidity of the environment. Furthermore, they were uptaken by HeLa cells and did not show any noticeable cytotoxicity even at high concentrations. For this reason, nanocarriers represent a promising approach for gene and medication delivery and the targeting of many pathological environments and specific intracellular compartments that are more acidic than the normal physiological conditions. The second approach (section 4.3) was based on the reaction between aqueous droplets containing the functionalized dextran and other aqueous droplets containing the water-soluble crosslinker. The formation of the hydrazone network led to the formation of nanogels by mixing the two types of precursor droplets. In addition to bearing two hydrazide groups able to create the pH-responsive network, those water-soluble crosslinkers also bear other functionality; the crosslinkers contained either a disulfide bond reactive in the presence of a reducing environment or a thioketal bonds responsive to the presence of reactive oxygen species. The resulting nanogels successfully encapsulated large payloads, and the release of the payload could be triggered by changes in acidity, the addition of dithiothreitol or glutathione as a reducing agent or by the addition of superoxide as Reactive oxygen species (ROS). The nanogels displayed limited toxicity and good uptake in HeLa cells. The results gathered and obtained in section (4.3) could pave the way for building desired multi-stimuli responsive polymer nanogels for specific tumor-targeting.en_GB
dc.language.isoengde
dc.relation.ispartofseriesPolysaccharide-Based pH-Responsive Nanocapsules Prepared with Bio-Orthogonal Chemistry and Their Use as Responsive Delivery Systems;paper-
dc.rightsInCopyright*
dc.rights.urihttps://rightsstatements.org/page/InC/1.0/?language=en*
dc.subject.ddc610 Medizinde_DE
dc.subject.ddc610 Medical sciencesen_GB
dc.subject.ddc660 Technische Chemiede_DE
dc.subject.ddc660 Chemical engineeringen_GB
dc.titleDeveloping bio-orthogonal chemistries to prepare nanocarriers for controlled releasede_DE
dc.typeDissertationde
dc.identifier.doihttp://doi.org/10.25358/openscience-5353-
jgu.type.dinitypedoctoralThesisen_GB
jgu.type.versionAccepted versionde
jgu.type.resourceTextde
jgu.date.accepted2020-11-09-
jgu.description.extentxiii, 132 Seitende
jgu.organisation.departmentMaxPlanck GraduateCenterde
jgu.organisation.year2020-
jgu.organisation.number9010-
jgu.organisation.nameJohannes Gutenberg-Universität Mainz-
jgu.rights.accessrightsopenAccess-
jgu.publisher.year2020-
jgu.publisher.nameAmerican Chemical Societyde
jgu.publisher.placeBiomacromoleculesde
jgu.publisher.urihttps://doi.org/10.1021/acs.biomac.0c00492de
jgu.publisher.isbn2764-2771de
jgu.organisation.placeMainz-
jgu.subject.ddccode610de
jgu.subject.ddccode660de
jgu.publisher.doi10.1021/acs.biomac.0c00492
jgu.organisation.rorhttps://ror.org/023b0x485
Appears in collections:JGU-Publikationen

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